Monday, May 27, 2013

DISCLAIMER: This is a hypothetical question and not a medical recommendation. But it might be an idea worth investigating in epidemiological studies.

Everyone knows that pot gives you the munchies. So the paradoxical finding that marijuana use is associated with a lower prevalence of obesity and diabetes came as a quite surprise to me. Now, a new study has concluded that pot smokers also have lower fasting insulin levels and smaller waistlines (Penner et al., 2013).

Marijuana use is increasingly common, and use of medical marijuana is now legal in 19 states and the District of Colombia.

Despite its associations with increased appetite and caloric intake, marijuana use also is associated with lower body mass index and prevalence of diabetes.

In a nationally representative survey population, we found current use of marijuana to be associated with lower levels of fasting insulin, lower insulin resistance (homeostasis model assessment of insulin resistance), and smaller waist circumference.

I will not address the issue of whether cannabis use is a risk factor for psychosis here.1 In fact, all of my observations will be related to the metabolic effects of marijuana and not to its psychoactive properties and possible detrimental effects on mental health.

Although cigarette smoking, alcohol use, unhealthy diet, and lack of exercise may contribute to shorter life expectancy in patients with serious mental illnesses (Lawrence et al., 2013), one has to wonder about the effects of atypicals on physical health.2 These drugs can have a very positive effect on mental health, but it comes at a cost.

Interestingly, cannabis use is not associated with greater mortality. In fact, the opposite has been reported by Koola et al. (2012), who "observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments."

A total of 762 patients with a psychotic disorder were included in that study. All were on atypical antipsychotics, and 39% used marijuana (although this is often under-reported). The authors speculated on the potential health benefits of cannabis, including its anti-inflammatory effects. However, they didn't mention reductions in obesity and diabetes as possible causes of lower mortality in cannabis users. This association bears further investigation, in my view.

Nevertheless, eliminating marijuana to counteract the increase in appetite brought on by atypicals seems like common sense. In fact, this has been proposed as a specific behavioral intervention (Werneke et al., 2013).

Those authors assumed that cannabis contributes to the weight gain caused by the prescription medication, which I also assumed (until reading the new papers cited here). But this relationship hasn't really been studied (Werneke et al., 2013):

As the endocannabioid system is linked to increased appetite and cannabioid receptor antagonists can induce weight loss [15] cannabis consumption will most likely potentiate antipsychotic-associated weight gain. As the prevalence of cannabis use in people suffering from psychosis is so high, the contribution of cannabis to weight gain in this population is likely to be significant. Surprisingly, this link between cannabis and weight gain remains largely ignored at present.

We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age. Here, we propose that this effect is directly related to exposure to the Δ9-tetrahydrocannabinol (THC) present in cannabis smoke. We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications.

These authors have filed a patent application for 'Use of marihuana and compounds therein for treating obesity' (which they acknowledge in the paper).

One of the same authors (Le Foll) has also published on 'Cannabis use and cannabis use disorders among individuals with mental illness' (Lev-Ran et al., 2013), which they found to be particularly high in individuals with Bipolar I disorder (especially in men).

To be completely clear, I am not advocating the use of marijuana by persons with schizophrenia or bipolar disorder. Rather, I am suggesting that the relationship between atypical antipsychotics and variables such as body mass index, waist circumference, insulin, glucose, and diabetes be compared between groups who do use cannabis vs. those who don't. If there is a benefit in the pot smokers, perhaps there could be a psychiatrically safe, cannabis-derived compound for weight loss in the future. Isn't that more likely than the development of 'third generation' antipsychotics that do not cause substantial weight gain?

Penner, E., Buettner, H., & Mittleman, M. (2013). The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults. The American Journal of Medicine DOI: 10.1016/j.amjmed.2013.03.002

"Prior work has shown that the analgesic acetaminophen, which acts indirectly through CB1 receptors, reduces the pain of social exclusion," Timothy Deckman of the University of Kentucky and his colleagues wrote in the study. "The current research provides the first evidence that marijuana also dampens the negative emotional consequences of social exclusion on negative emotional outcomes."

You could be forgiven if you thought, as I initially did, that the University of Kentucky IRB must hold a liberal view on the administration of controlled substances to undergrads participating in psychology experiments. But that's not what happened here... the data are entirely correlational, based on self-report, and largely problematic (in my view).

Marijuana Lowers Self-Worth and Worsens Mental Health in Those Who Are Not Lonely

That's my interpretation of the article, which is SO clunky compared to the fun and breezy query, Can Marijuana Reduce Social Pain?2

The paper begins with the premise that "Social and physical pain share common overlap at linguistic, behavioral, and neural levels" (Deckman et al., 2013). So let's give a pain reliever to reduce the sting of rejection! A critique of the original work asked why the authors chose Tylenol, as opposed to an NSAID like aspirin, ibuprofen, or naproxen. In the current study they tried to develop a mechanistic account of why acetaminophen might reduce social pain:

Prior research has shown that acetaminophen—an analgesic medication that acts indirectly through cannabinoid 1 receptors—reduces the social pain associated with exclusion. Yet, no work has examined if other drugs that act on similar receptors, such as marijuana, also reduce social pain.

The problem is that acetaminophen's mechanism of action is surprisingly unclear (Toussaint et al., 2010). One prominent hypothesis claims that Tylenol might exert its analgesic effects through descending serotonergic pathways at the level of the spinal cord. In fact, the paper that Deckman et al. cited in favor of cannabinoid 1 (CB1) receptors describes a very complex pathway that includes indirect involvement of CB1, with actual pain suppression occurring in the spinal cord.3

An even more basic question: if acetaminophen acts through CB1 receptors, then why isn't it a potential drug of abuse, or known by experienced pharmanauts for its psychoactive properties? The drug experience vault Erowid says:

Acetaminophen is a non-salicylate analgesic and antipyretic (pain killer and fever reducer). It is a common over-the-counter pain medication found in hundreds of products around the world. At higher doses it is known to cause liver-damage and has a low therapeutic index (ratio of effective dose to toxic dose), making it dangerous when included in recreationally used pharmaceuticals [e.g., Tylenol with codeine]. It is not known to be psychoactive.

On the other hand, we all know that cannabis is psychoactive. The design of the cannabis study included cross-sectional national survey data, a two year longitudinal survey of 400 high school students, and a Mechanical Turk-implemented version of cyberball, an online game to simulate social exclusion. In all cases, participants reported their marijuana use, and this was related to the variables of interest.

I'll focus on the national survey data in this post, which comprised Study 1 (Marijuana Use Buffers Lonely People From Lower Self-Worth and Self-Rated Mental Health) and Study 2 (Marijuana Use Predicts Fewer Major Depressive Episodes Among the Lonely).

Study 1 used data from the National Comorbidity Survey: Baseline (NCS-1), 1990-1992 (ICPSR 6693), which you can download for yourself. The survey recruited 8,098 individuals from the ages of 15 to 54 living in the U.S., and included over 4,000 variables. Only four variables were chosen for the present study: self-reported loneliness (1= often, 4 = never), marijuana use (0 = none, 1 = daily, 8 = once or twice a year), self-worth (1 = high, 4 = low), and overall mental health (1 = excellent, 5 = poor).

Loneliness was used as a proxy for social pain. Contrary to what the headlines suggested, the impact of pot smoking on social pain was not directly examined. Instead, the study assessed the effects of loneliness (high, low), marijuana use (high, low) and their interaction on self-worth and mental health.

Loneliness and pot smoking interacted to predict feelings of self-worth [B = 0.03, t(5609) = 2.20, p = .03]. Given the huge number of participants, this level of statistical significance is not very impressive.

For lonely people, the amount of pot smoked didn't make too much of a difference in their self-worth (see red arrow above). For socially connected people, greater marijuana use resulted in lower self-worth, although it's not clear this was significant (pairwise statistical tests were not reported).

I also question how the High Marijuana Use and Low Marijuana Use groups were determined, because over 5,000 participants did not smoke pot at all in the last 12 months. Does the heavy use group combine those who smoke 6 joints a year with those who smoke daily?

Table depicting the mean level of loneliness (1=often to 4=never) for participants at 9 levels of pot smoking (0=none, 1=daily, 8=once or twice a year). Unlike the figure above, the values were not reverse-scored. Data from the National Comorbidity Survey: Baseline (NCS-1), 1990-1992 (ICPSR 6693).

In the lonely group, the frequency of marijuana use had even less of an impact on self-rated mental health. In contrast, heavy pot use resulted in worse mental health among the socially connected. A modest loneliness by marijuana use interaction was observed for mental health [B = 0.03, t(5609) = 2.07, p = .04], similar to what was seen for self-worth.

Looking at Fig. 2 above, it's clear that marijuana use does not buffer the lonely from the negative consequences of social pain: the black circle and gray square are overlapping. But the authors interpret this result differently:

Marijuana use buffered the lonely from both negative self-worth and poor mental health. This evidence suggests that at relatively high levels of social pain, marijuana use lessens negative consequences of social pain.

As part of the six sentence Discussion of Study 1, they point out one weakness to motivate Study 2:

This study contained some limitations. First, it only assessed self-ratings of both self-worth and mental health. If marijuana use weakens the relationship between social pain and self-reported psychological well-being, then there should also be a lower rate of validated clinical diagnoses of poor psychological well-being.
. . .
To address the limitation of Study 1, Study 2 sought to show that marijuana buffered lonely participants from experiencing a standardized diagnosis of poor psychological well-being. Study 2 used a different nationally representative sample from Study 1 to test this hypothesis.

HOWEVER, the dataset used in Study 1 has extensive information on DSM-III-R diagnoses (including depression) for the majority of participants, so I'm not sure why this wasn't included. Study 2 used data from the National Comorbidity Survey Replication (NCS-R; Kessler & Merikangas, 2004), a different national sample of 10,000 respondents.

Speaking of replication, Deckman et al. should have been able to completely replicate the pot × loneliness analyses for self-worth, self-rated mental health, and DSM depression in both National Comorbidity Samples. I'm not sure why they didn't.

For Study 2, non-users were excluded (unlike in Study 1). The final sample included 537 participants with info on loneliness, marijuana use, and whether they experienced a major depressive episode during the past year. Once again, the results demonstrated that if you're lonely, smoking a lot vs. a little pot will not affect whether you'll experience a major depressive event (red arrow below). If you're not lonely, heavy marijuana use increases the risk of major depression.

Fig. 3 (modified from Deckman et al., 2013). Study 2: Marijuana use moderates the relationship between loneliness and a having a DSM-IV major depressive event in the past 12 months.

Study 3, a survey of 400 high school students, was the most puzzling of all. At Time 1 the students were asked about loneliness, lifetime marijuana use, and depression. Two years later, they were asked again about depression, using the Behavior Assessment System for Children (second edition), but not about marijuana use and loneliness (which could have changed drastically in 2 years).

At any rate, lonely heavy pot users were the least depressed of all at Time 2. I'm not sure how to interpret this; the pattern differs from what was seen in adults. Maybe the lonely heavy pot users at Time 1 bonded with their peer group over two years and were no longer lonely at Time 2.

Fig. 4 (modified from Deckman et al., 2013). Study 3: Marijuana use moderates the relationship between loneliness and depression over 2 years in adolescents.

Conflicting earlier studies in adolescents have suggested that lonely high school students are more likely (Page, 2000) and less likely (Grunbaum et al., 2000) to use marijuana. A recent study indicated that heavy marijuana users are more likely to engage in self-injury (Giletta et al., 2012), but this was true only for Americans and not for Dutch and Italian students. I imagine there's a huge literature on these issues, but it wasn't addressed at all in the present paper.

Overall, I don't think the authors have demonstrated that marijuana reduces social pain, at least not in adults. They used a very select set of questions from huge, comprehensive national surveys and then called this a limitation of the study:

Another potential limitation to some of the above studies lies in how social pain was measured. In Studies 1–3, single-item measures of loneliness were used as a proxy for social pain. These studies use large community sample data sets and thus our ability to include numerous measures was limited.

There were many other questions that could have assessed social pain in NCS-1 and NCS-R, including a series of questions about friendships, e.g. "How much do your friends really care about you--a lot, some, a little, or not at all?"

Has this paper advanced the agenda of the social pain/physical pain isomorphists? We already knew that opiates were good at alleviating both types of pain. And it's a truism to say that people turn to alcohol and all sorts of recreational drugs to dull the pain of a lonely existence. For the most part, we assume this isn't a healthy way to cope. Some studies suggests that depression is decreased in heavy marijuana users (Denson & Earleywine, 2006) but others find an increase (Pacek et al., 2013).

In sum, Deckman et al., (2013) presented evidence that heavy marijuana use is detrimental to the mental health of socially connected individuals and not especially effective in buffering lonely users from social pain.

LONELY - During the past 30 days how often did you feel lonely?
POT - On the average, how often in the past 12 months have you used marijuana or hashish? Just
WORTHY - I feel I am a person of worth, at least equal with others.
MENTAL HEALTH - How would you rate your overall mental health? Is it excellent, very good, good, fair, or poor?

Data for these four questions were available from 5,631 participants. Ratings were standardized, reverse-scored, and analyzed using weighted least squares regression.

...While DSM has been described as a “Bible” for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been “reliability” – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.

Instead, the Research Domain Criteria (RDoC) framework would become the preferred method for organizing biologically-based research on mental illnesses, with the ultimate goal of constructing a new classification scheme.

NIMH and APA have a shared interest in ensuring that patients and health providers have the best available tools and information today to identify and treat mental health issues, while we continue to invest in improving and advancing mental disorder diagnostics for the future.

Today, the APA's Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders Patients, families, and insurers can be confident that effective treatments are available and that the DSM is the key resource for delivering the best available care. The NIMH has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states, “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

Yet, what may be realistically feasible today for practitioners is no longer sufficient for researchers. Looking forward, laying the groundwork for a future diagnostic system that more directly reflects modern brain science will require openness to rethinking traditional categories. It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. This is the focus of the NIMH’s Research Domain Criteria (RDoC) project. RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness.

So what is RDoC, and how might it be applied to new research projects? From the DSM perspective of categorical disorders (e.g, schizophrenia, major depression, and obsessive compulsive disorder), RDoC embraces diagnostic messiness. Patients previously excluded from a study due to comorbidities, or because they don't meet full criteria? Misfits from the "Not Otherwise Specified" (NOS) category? Now they're in. Specifically, the instructions for RFA-MH-14-050 state:

Priority will be given to applications that have a well-justified plan to include patients from multiple diagnostic groups (including Not Otherwise Specified and forme fruste diagnoses) as appropriate for explicating the dimensions and constructs of interest in the study design. Studies that include patients from a single diagnostic group may also be considered if there is a particularly strong justification for examining constructs of interest within one diagnostic category. A defensible approach might be to study all patients presenting themselves at a specialty clinic, e.g., mood disorders clinic, anxiety clinic, or psychotic disorders clinic, regardless of whether they meet criteria for a particular DSM diagnosis.

One potential pitfall of this approach is the money required to enroll huge numbers of patients. If commonalities in cognitive function or brain circuitry or especially genetic risk factors are to emerge from studying all patients with mood disorder-like symptoms, then sample sizes must be very large to overcome potential noise in the system(s).

The applicant would propose to study one or more of the five different domains, or constructs, that have been fleshed out at NIMH Workshops:

The possible units of analysis run the gamut from genes to circuits to behavior, and the studies should use specific tasks (paradigms) and self-report measures, as shown in the Negative Valence Systems matrix below.

Animal models of active threat ("fear") like the startle response are pretty well established and would allow a much more detailed analysis of mechanisms, from genes to behavior. In the realm of human research, one example of a proposed project for RFA-MH-14-050 is:

Evaluation of the relationship between measures of exaggerated fear response, reports of overall distress and anxiety, and chronicity of internalizing disorders

This project could study common and unique aspects of the startle response in patients with phobias, panic disorder, OCD, generalized anxiety, and major depression ("internalizing disorders"), as described in this review article (Vaidyanathan et al. 2011).

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

The idea is to find common neurobiological substrates of altered reward circuitry that cut across DSM-esque categories (e.g., drug and alcohol use disorders, serious gambling problems, mania), where individuals seek out reward without regard to the consequences. At the other end of the spectrum is anhedonia, or the inability to feel pleasure from previously rewarding activities. Anhedonia is often (but not always) seen in major depression and schizophrenia, two disorders usually considered to have little overlap.

Will RDoC succeed in carving out a new nosology and generating a new guidebook? Will it lead to diagnostic tests that can identify specific cognitive, emotional, motivational, or social weaknesses that can be treated with targeted pharmaceuticals, deep brain stimulation, and/or improved psychotherapies?

This quote from Chapter 1 of a 2002 white paper collection indicates the DSM-5 revision committee (a joint APA / NIMH production) didn't exactly expect that all of its goals would be reached (PDF):

"Given the relatively short time frame for generating breakthrough research findings between now [1999] and the probable publication of DSM-V in 2010 [2013], it is anticipated that some of the research agendas suggested in these chapters might not bear fruit until the DSM-VI or even DSM-VII revision processes!"

May 6Matthew Herper (Forbes reporter covering science and medicine): “I spoke to NIMH. This is a broadening, not an exclusion.” ...

DSM-5 Task Force member Dr. David J. Kupfer strikes back in the NYT, blaming NIMH and the sluggish rate of scientific progress: “The problem that we’ve had in dealing with the data that we’ve had over the five to 10 years since we began the revision process of D.S.M.-5 is a failure of our neuroscience and biology to give us the level of diagnostic criteria, a level of sensitivity and specificity that we would be able to introduce into the diagnostic manual.”

May 7
“Some people have the idea that we’re trying to ditch or diss the DSM and that’s not a fair assessment,” says Insel.

Dr. Bruce Cuthbert: “The sensationalist headlines out there are entirely misleading, and we will continue to support DSM-based research as we increase our portfolio of RDoC grants. RDoC is intended to inform future versions of the ICD and DSM; we have no intention of coming out with a competing system. The implication of this is that the fruits of RDoC are likely to be taken up into the ICD/DSM piecemeal rather than in one entire set, at such times as the evidence for various aspects becomes strong enough to warrant changes to the nosologies.”

Dr. Thomas Insel: “We cannot ‘ditch’ or ‘reject’ terms like schizophrenia or bipolar. We just need to view them as constructs, perhaps including many different disorders that require different treatments or obscuring disorders than cut across the current categories. A symptom-only system will not be sufficient for identifying brain disorders—whether the initial label is dementia or schizophrenia.”

Dr. Cuthbert: “As with most shifts in science, changes in research priorities require a transition. Because almost all clinical researchers today grew up with the DSM system both clinically and in research, it will take some time to get a “feel” for the relationships between DSM disorders and various kinds of RDoC phenomena (both in terms of the types of symptoms, and in overall severity), learn how to write grant applications with the new criteria, and evolve new review criteria. So, there will be a period of some time while these crosswalks are worked out.”

May 8Dr. Cuthbert: “Using DSM diagnoses for research has become a de facto standard ever since the DSM-III came out in 1980. What we are trying to do is to study neural systems directly because they cut across lots of the dsm disorders. ... We are moving in a new direction. That doesn’t mean that next month we’ll stop accepting DSM diagnoses. It rather is a shift in emphasis.”

...While DSM has been described as a “Bible” for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been “reliability” – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment.

Patients with mental disorders deserve better. NIMH has launched the Research Domain Criteria (RDoC) project to transform diagnosis by incorporating genetics, imaging, cognitive science, and other levels of information to lay the foundation for a new classification system. Through a series of workshops over the past 18 months, we have tried to define several major categories for a new nosology...

There is no absolute timeline of when these [research] advances might occur. Instead of providing an immediate replacement for DSM and its clinical diagnoses, RDoC is a long-term project to help the research community by defining more biologically based organizational principles for various psychopathologies...

Now, in a move sure to rock psychiatry, psychology and other fields that address mental illness, the director of the National Institutes of Mental Health has announced that the federal agency–which provides grants for research on mental illness–will be “re-orienting its research away from DSM categories.” Thomas Insel’s statement comes just weeks before the scheduled publication of the DSM-V, the fifth edition of the Diagnostic and Statistical Manual.

Note the foreshadowing here: I do think Dr. Insel's timing in announcing the dimensional RDoC was a deliberate attempt to blunt the media circus that will surround the big DSM-5 release at the APA meeting in 2 weeks.

However, Horgan thinks the timing was more related to President's Obama's ambitious new BRAIN Initiative when he says:

NIMH director Insel doesn’t mention it, but I bet his DSM decision is related to the big new Brain Initiative, to which Obama has pledged $100 million next year. Insel, I suspect, is hoping to form an alliance with neuroscience, which now seems to have more political clout than psychiatry.

Do they really think that we won’t notice that the APA and NIMH are working in tandem – that their efforts are coordinated? Do they think we won’t notice that the "cross cutting" dimensional scheme for the DSM-5 that got dropped is the same idea as the RDoC? The articles that have been popping up all day are playing this as Insel’s NIMH throwing the DSM-5 under the bus. No need. The DSM-5 is already under the bus where it belongs.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.